Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

those that are of low penetrance. High-penetrance variants by definition have a large effect on phenotype, and therefore iden- tifying these variants usually provides fundamental insights into pathobiology. Because individuals carrying high-penetrance variants have a high probability of expressing a disease pheno- type, such variants tend to be rare and to segregate in families and are generally most powerfully mapped using pedigree- based approaches (see Fig. 1.7-1). In contrast, low-penetrance variants have a relatively weak effect on phenotype, and there- fore identification of individual low-penetrance variants may, at least initially, provide relatively little new biological knowledge. However, because of their small effects, such variants are typi- cally common in the population, and therefore identifying them may add to our understanding of disease risk in the population as a whole. Because we do not expect these variants to segre- gate strongly with the disease phenotype in pedigrees, efforts to identify them focus on population samples. Pedigree Analysis A pedigree analysis, which is conducted in multigenerational families, consists of scanning the genome or a portion of the genome with a series of markers in one or more affected pedi- grees, calculating a LOD score at each marker position, and identifying the chromosomal regions that show a significant deviation from what would be expected under independent assortment. The primary goal of pedigree analysis is to deter- mine if two or more genetic loci (i.e., a genetic marker of known location and the unknown disease loci) are cosegregating within a pedigree. Following the successful application of pedigree analysis to map Mendelian disorders such as Huntington’s disease, many investigators adopted this strategy for mapping psychi- atric disease genes with, at best, mixed success. In the late 1980s and mid-1990s, several pedigree-based studies reported the mapping of susceptibility loci for Alzheimer’s disease, bipolar disorder, and schizophrenia. Although the linkage findings for three Alzheimer’s disease loci were relatively quickly replicated, the findings reported for bipolar disorder and schizophrenia were ultimately determined to have been false positives. A number of different explanations have been proposed for the failure of pedigree-based approaches to map psychiatric loci; however, most investigators now recognize that these studies were generally drastically underpowered considering the apparent etiological complexity of psychiatric disorders. Pedigree analysis in psychiatry has increasingly turned toward an application that is more appropriately powered, namely, the mapping of quantitative trait loci (QTLs). QTLs are defined as genetic loci that contribute to the variation in con- tinuously varying traits (as opposed to categorical traits such as disease diagnoses). QTLs are typically loci of small effect that only contribute to a portion of the observed variance of a trait in the population. It is now generally accepted that, using analytical methods developed in the late 1990s, it may be pos- sible to use pedigree studies to map a wide range of quantitative traits that are relevant for understanding psychiatric disorders. Several such studies are now being undertaken, typically with multiple phenotypes being assessed in each individual in the pedigree.

human polymorphisms. Because of the existence of LD, one can use data from a subset of genotyped polymorphisms to infer genotypes at nearby loci. Clusters of alleles that are in LD and inherited as a single unit are termed haplotypes. Thus LD map- ping “consolidates” genomic information by identifying haplo- types in populations that can then be used to infer IBD sharing among unrelated individuals. There are several methods to measure the extent of LD. One of the most commonly used measures of LD is r 2 , a measure of the differ- ence between observed and expected haplotype probabilities. Unlike D ′ , another widely used measure of LD, r 2 values do not depend on the allele frequencies of the loci being assessed. A large r 2 value indi- cates that the observed frequency of association between two alleles is greater than that expected by chance; that is, the alleles are in LD. LD studies have traditionally been used to complement traditional pedigree analyses, for example, to hone in on a locus that has been mapped by linkage analysis. However, LD-based association analysis has become the method of choice for whole genome screens, particularly for dis- eases where traditional linkage studies have been unsuccessful. These studies have one great advantage over a traditional family analysis: because affected individuals are chosen from an entire population rather than from one or a few pedigrees, the number of potential sub- jects is limited only by the size of the population and the frequency of the disease. Maximizing the potential number of affected individuals that can be included in the analysis is extremely important for disorders where genetic heterogeneity or incomplete penetrance is likely to be a factor. Genetic Markers Mapping studies, regardless of their type, depend on the avail- ability of genetic markers. The most widely used markers are microsatellite markers (also called simple tandem repeats [STRs], or simple sequence length polymorphisms [SSLPs]) and single nucleotide polymorphisms (SNPs). SSLPs are stretches of variable numbers of repeated nucleotides two to four base pairs in length. These markers are highly polymor- phic, as the number of repeat units at any given STR locus varies substantially between individuals. SNPs, as the name implies, are single base pair changes at a specific nucleotide; they are the most common form of sequence variation in the genome. SNPs are widely used for genetic mapping studies because they are distributed so widely across the genome and because they can be assessed in a high-throughput, automated fashion. Other forms of genetic variation that have been investigated for use as genetic markers include small insertion or deletion polymor- phisms, termed indels, that generally range between 1 and 30 base pairs and copy number variations (CNVs), which can refer to either deletions or duplications. Recent genomewide surveys have revealed that CNVs are common and can range in length from several base pairs to several million base pairs. CNVs may contribute to chromosomal recombination and rearrangements, thereby playing an important role in generating genetic diver- sity, and also, as many of these variants are sizable, it is hypoth- esized that they may significantly influence the expression of genes that encompass or are adjacent to the variant. Mapping Strategies The genetic variants that contribute to disease susceptibility can be roughly categorized into those that are highly penetrant and